The overall goal of this Program Project Grant is to determine the molecular mechanisms involved in the chemoprevention of cancer by non-steroidal anti-inflammatory drugs (NSAIDs). We will specifically test the hypothesis that the cyclooxygenase (COX) pathway and/or its eicosanoid products play a role in certain aspects of breast, cervical, ovarian and colorectal carcinogenesis. These solid malignancies lead to a large number of deaths each year. Better detection and prevention strategies are needed. NSAIDs have effects on model systems for these diseases. Cyclooxygenase enzymes are known targets for NSAIDs. Two isoforms of cyclooxygenase have been characterized and they are referred to as Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) in this proposal. The goals of this program are to test the hypothesis that COX enzymes or their eicosanoid products play a role in carcinogenesis and to determine the molecular mechanisms by which NSAIDs prevent colorectal cancer and prostaglandin production increases risk for neoplasia. Here we provide an overview of the projects proposed to test this hypothesis and highlight how planned interactions among the investigators will aid significantly in the success of this program project. There are four projects and three cores included in this competing renewal Program Project Grant application. Research Projects 1. Role of COX downstream signaling pathways in cancer 2. COX-2: A target for the prevention of cervical cancer 3. COX-2 regulation and function in tumor biology 4. COX-1: A target for ovarian cancer prevention and treatment Cores A. Administrative Core B. Eicosanoid Analysis Core C. Animal and Molecular Biology Core